Complex inorganic and organic compounds, e.g., drugs, monomers, organometallic compounds, semiconductors, polymers, peptides, oligonucleotides, polynucleotides, carbohydrates, amino acids, and nucleic acids belong to a class of materials having significant diagnostic, medicinal and commercial importance. Many techniques have been developed to produce these materials. However, the systems necessary to carry-out and prepare or synthesize these complex materials are inefficient, wasteful and often times require reagent quantities far in excess of what is available. This is especially the case in those instances where milliter quantities are involved. The use of conventional substrates requires larger sized systems with the incumbent process control problems. Additionally, reagent or reactant stability must be considered and accurately controlled to render the process efficient in yield and cost.
The production of these complex materials requires a versatile system that can handle different reaction and separatory schemes. Most synthesizers provide only for a single type of reactor, e.g., electrochemical, catalytic, solid phase support, enzymatic, photochemical, or hollow chamber.
For example, U.S. Pat. No. 4,517,338 to Urdea teaches a system for sequencing amino acids that uses one or more elongated tubular reaction zones. The reactors for each reaction zone are similar in structure with an internal diameter (I.D.) of a 0.1 to 1.0 cm. Each of the reactors needs a glass frit to support the solid-phase material.
U.S. Pat. No. 4,960,566 to Mochida relates to an automatic analyzer for conveying reagent coated capillary tubes along process lines where reagents are added, reacted and analyzed. The Mochida patent indicates at Column 3 that the inner diameter of the capillary tubes appears to be no smaller than 0.95 mm. The process of Mochida provides for serial processing of reaction tubes of a common design. Independent temperature control of parallel tubes and modularity are not provided.
U.S. Pat. No. 4,276,048 to Leaback teaches capillary size reaction containers for volumetric transfer of fluids to a microtitre tray. The system is essentially batch-like and does not involve continuous flow or automatic valving to selectively direct the flow of a particular reagent to one reaction column as opposed to another to provide for amino acid sequencing within the tube.
U.S. Pat. No. 5,176,881 to Sepaniak et al. teaches a fiber optic-based regenerable biosensor that uses a capillary feed mechanism.
U.S. Pat. No. 4,362,699 to Verlander et al. relates to high pressure peptide synthesizers and uses a plurality of reservoirs that communicate via a switching valve to a reactor 90. The Verlander system was designed to overcome the limitations of the Merrifield system which apparently had a limitation of synthesizing peptides having no more than 10 amino acids. The system can also include a mixer upstream of the reactor to mix the protected amino acid solution and the appropriate activating reagent. Column 6 lines 3-12. The system is automated and the reactor column contains a polystyrene resin which is derivatized with a protected amino acid.
U.S. Pat. No. 4,458,066 to Caruthers et al. teaches an amino acid synthesizer and uses a plurality of reagent reservoirs connected via a manifold to a tubular reactor. The reactor column 10 includes a solid silica gel matrix derivatized for the sequencing operation and, via a valve can be communicated to a UV detector 58. The reactor is taught to be sized for a 1 ml. volume.
U.S. Pat. No. 4,728,502 Hamill relates to an amino acid sequencer that utilizes a plurality of stacked disks each having a plurality of chambers and resulting in a plurality of parallel columns. Although the contents of each chamber of each disk are removable, the respective columns formed by a series of chambers in the stacked disk are not.
U.S. Pat. No. 4,961,915 to Martin relates to a DNA sequencing system. A rotatable turntable conveys fluids along narrow channels that are open on an upper end. This allows individual dispensing of additional reagents along the length of the channel. The Martin patent does not provide a continuous flow valved reaction system or direct in-line valving to control reagents directly to one or more channels. In addition, the grooves or channels are in a common base and replacement or scale up is not possible.
The object of the subject invention is to provide an Integrated Chemical Synthesizer (ICS) system that is modular in design and provides for continuous flow operation. The modular nature of the ICS system allows for the use of one or more of the same type of reactor, or a variety of different types of reactors, each having microliter capacity. The reactors of the ICS system are capable of being used individually, together, and interchangeably with one another and can be of the thermal, electrochemical, catalytic, enzymatic, photochemical, or hollow chamber type. The modular nature of the system, component parts, e.g., the reactors, flow channels, sensors, detectors, temperature control units, allows easy replacement and/or interchangeability of the component parts and provides a versatility not offered by existing systems.
The ICS system provides for uniform temperature control for continuous flow reactors under elevated pressures. This allows for precise control of residence time within a reaction zone. ICS synthesizers would thus exhibit a number of advantages when compared to conventional systems of larger size. Heat transfer, which depends upon the ratio of surface area (A) to volume (V), would be much better for the smaller reactors. This is a major advantage, for example, in capillary zone electrophoresis compared to large scale gel electrophoresis. This configuration also allows faster heat dissipation and faster thermal control.
The ICS system would not only present better control of reaction conditions, but it would allow for quenching reactions at certain stages to prevent further reaction. The ICS system would also, due to its modular nature, provide for serial placement of reactors to allow controlled sequential reactions of intermediates. Moreover, it should be much easier to scale-up reactions based on the ICS approach because one would simply add additional modules of exactly the same type to increase output. For industrial synthesis, the ICS approach would eliminate proceeding from a bench scale reactor through a variety of different pilot plant configurations to a full-sized reactor.
Moreover, the inherent redundancy of multiple parallel ICS reactors implies fewer operational problems with the failure of a few reactors, especially if the system is set up for easy replacement and repair of a single ICS line. As a result, such systems are probably inherently much safer. The rupture of a single ICS reactor, even at high temperature and pressure, would cause negligible damage since the total volume and amounts of reactants released would be small. This would be especially beneficial when carrying out reactions under extreme conditions, e.g., the high temperatures and pressure in supercritical water and other fluids. Overall the ICS system should result in better yields of products with less waste and disposal problems because of better control of reaction variables.
As a result of the ICS modular system, the problems of inefficiency, lack of versatility, down-time, reagent/reactant waste and excessive cost have been overcome.